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Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver–Russell syndrome and growth retardation
  1. Karen Grønskov1,
  2. Rebecca L Poole2,3,
  3. Johanne M D Hahnemann1,
  4. Jennifer Thomson4,
  5. Zeynep Tümer1,
  6. Karen Brøndum-Nielsen1,5,
  7. Rinki Murphy6,
  8. Kirstine Ravn1,
  9. Linea Melchior1,
  10. Alma Dedic1,
  11. Birgitte Dolmer7,
  12. I Karen Temple2,3,
  13. Susanne E Boonen1,8,
  14. Deborah J G Mackay2,3
  1. 1Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark
  2. 2Wessex Genetics Service, Southampton University Hospitals Trust, Southampton, Salisbury Hospital NHS Foundation Trust, Salisbury, UK
  3. 3Division of Human Genetics, University of Southampton, Southampton, UK
  4. 4Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK
  5. 5Genetic Counseling Clinic, The Kennedy Center, Glostrup, Denmark
  6. 6Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
  7. 7Department of Pediatrics, Næstved Hospital, Næstved, Denmark
  8. 8The Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
  1. Correspondence to Dr Karen Grønskov, The Kennedy Center, Gl, Landevej 7, Glostrup, DK-2600, Denmark; kag{at}kennedy.dk

Abstract

Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0.

Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS.

This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.

  • Silver–Russell syndrome
  • H19 enhancer
  • deletion
  • methylation
  • diagnosis
  • molecular genetics

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Southampton and South West Hampshire research ethics committee 07/H0502/85.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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